Note: Descriptions are shown in the official language in which they were submitted.
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SKIN-PERMEABLE SELECTIVE CYCLOOXYGENASE-2 INHIBITOR
COMPOSITION
FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions containing a
selective cyclooxygenase-2 (COX-2) inhibitory drug, in particular to such
compositions that are suitable for administration to skin to provide a local
or systemic
therapeutic effect. The invention also relates to processes for preparing such
compositions and to methods of treatment comprising administration of such
compositions to skin of a subject in need thereof.
BACKGROUND ~OF THE INVENTION
Inhibition of cyclooxygenase (COX) enzymes is believed to be at least the
primary mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) exert
their characteristic anti-inflammatory, antipyretic and analgesic effects,
through
inhibition of prostaglandin synthesis. Conventional NSAIDs such as ketorolac,
diclofenac, naproxen and salts thereof inhibit both the constitutively
expressed
COX-1 and the inflammation-associated or inducible COX-2 isoforms of
cyclooxygenase at therapeutic doses. Inhibition of COX-l, which produces
prostaglandins that are necessary for normal cell function, appears to account
for
certain adverse side effects that have been associated with use of
conventional
NSAIDs. By contrast, selective inhibition of COX-2 without substantial
inhibition of
COX-1 leads to anti-inflammatory, antipyretic, analgesic arid other useful
therapeutic
effects while minimizing or eliminating such adverse side effects. Selective
COX-2
inhibitory drugs have therefore represented a major advance in the art.
Numerous compounds have been reported having therapeutically and/or
prophylactically useful selective COX-2 inhibitory effect, and have been
disclosed as
having utility in treatment or prevention of specific COX-2 mediated disorders
or of
such disorders in general. Among such compounds are a large number of
substituted
pyrazolyl benzenesulfonamides as reported in U.S. Patent No. 5,466,823 to
Talley et
al., including fox example the compound 4-[5-(4-methylphenyl)-3-
(trifluoromethyl)-
1H-pyrazol-1-yl]benzenesulfonamide, also referred to herein as celecoxib (I),
and the
compound 4-[5-(3-fluoro-4-methoxyphenyl)-3-difluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide, also referred to herein as deracoxib (II).
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CF3
(I) (II)
Other compounds reported to have therapeutically and/or prophylactically
useful selective COX-2 inhibitory effect are substituted isoxazolyl
benzenesulfonamides as reported in U.S. Patent No. 5,633,272 to Talley et al.,
including for example the compound 4-[5-methyl-3-phenylisoxazol-4-
yl]benzenesulfonamide, also referred to herein as valdecoxib (III).
(III)
Still other compounds reported to have therapeutically and/or prophylactically
useful selective COX-2 inhibitory effect are substituted
(methylsulfonyl)phenyl
furanones as reported in U.S. Patent No. 5,474,995 to Ducharme et al.,
including for
example the compound 3-phenyl-4-[4-(methylsulfonyl)phenyl]-5H-furan-2-one,
also
referred to herein as rofecoxib (IV).
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U.S. Patent No. 5,981,576 to Belley et al. discloses a further series of
(methyIsulfonyl)phenyl furanones said to be useful as selective COX-2
inhibitory
drugs, including 3-(1-cyclopropylmethoxy)-5,5-dimethyl-4-[4-
(methylsulfonyl)phenyl]-5H-furan-2-one and 3-(1-cyclopropylethoxy)-5,5-
dimethyl-
4-[4-(methylsulfonyl)phenyl]-5H-furan-2-one.
U.S. Patent No. 5,861,419 to Dube et al. discloses substituted pyridines said
to
be useful as selective COX-2 inhibitory drugs, including for example the
compound
5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine, also
referred
to herein as etoricoxib (V).
(V)
European Patent Application No. 0 863 134 discloses the compound 2-(3,5-
difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-I-one said to be
useful
as a selective COX-2 inhibitory drug. International Patent Publication No.
WO 99/11605 discloses 5-alkyl-2-arylaminophenylacetic acids and derivatives
thereof, including the compound 5-methyl-2-(2'-chloro-6'-
fluoroanilino)phenylacetic
acid and salts thereof, said to be selective inhibitors of COX-2.
U.S. Patent No. 6,034,256 to Carter et al. discloses a series of benzopyrans
said to be useful as selective COX-2 inhibitory drugs, including the compound
(S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (VI).
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O
(VI)
International Patent Publication No. WO 00/24719 discloses substituted
pyridazinones said to be useful as selective COX-2 inhibitory drugs, including
the
compound 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-
(methylsulfonyl)phenyl]-3-(2H)-pyridazinone.
Selective COX-2 inhibitory drugs have been formulated in a variety of ways,
principally for oral delivery. However, topical administration of such drugs
has been
suggested in general terms, for example in some of the above-cited patents.
Above-cited U.S. Patents No. 5,466,823 and No. 5,633,272 disclose that their
subject compounds, which include celecoxib and valdecoxib, can be delivered
topically. It is further disclosed in these patents that the compounds may be
dissolved
in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed
oil,
peanut oil, sesame oil and benzyl alcohol.
Above-cited U.S. Patent No. 5,474,995 discloses that its subject compounds,
which include rofecoxib, can be formulated as creams, ointments, jellies,
solutions or
suspensions for topical use. Above-cited U.S. Patent No. 5,861,419 similarly
discloses that its subject compounds, which include etoricoxib, can be
formulated as
creams, ointments, jellies, solutions or suspensions for topical use, and
further
suggests that topical formulations may generally be comprised of a
pharmaceutical
carrier, co-solvent, emulsifier, penetration enhancer, preservative system and
emollient.
Above-cited U.S. Patent No. 6,034,256 discloses that its subject compounds,
which include (S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-
carboxylic
acid and salts thereof, can be applied as a topical ointment or cream for
treatment of
inflammations of external tissues, e.g., skin.
U.S. Patent No. 5,932,598 to Talley et al. discloses a class of water-soluble
prodrugs of selective COX-2 inhibitory drugs, including the compound N-[[4-(5-
methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide, also referred to
herein as
parecoxib (VII), and salts thereof, for example the sodium salt, referred to
herein as
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parecoxib sodium. Parecoxib converts to the substantially water-insoluble
selective
COX-2 inhibitory drug valdecoxib following administration to a subject.
Parecoxib
itself shows weak in vitro inhibitory activity against both COX-1 and COX-2,
while
valdecoxib (II) has strong inhibitory activity against COX-2 but is a weak
inhibitor of
COX-1.
(VII)
Because of the high water solubility of parecoxib, particularly of salts such
as
parecoxib sodium, by comparison with most selective COX-2 inhibitory drugs
such as
celecoxib and valdecoxib, the prodrug parecoxib has been proposed fox
parenteral
use. See Talley et al. (2000), J. Med. Chem. 43, 1661-1663.
Above-cited U.S. Patents No. 5,932,59 and No. 6,034,256 disclose that their
subject compounds can be applied as a topical ointment or cream for treatment
of
inflammations of external tissues, e.g., skin. It is further disclosed therein
that the
aqueous phase of a cream base for such purpose may include at least 30% by
weight
I5 of a polyhydric alcohol such as propylene glycol, butane-1,3-diol,
mannitol, sorbitol,
glycerol, polyethylene glycol and mixtures thereof, and that the topical
formulation
may include a dermal penetration enhancer such as dimethylsulfoxide. It is
still
further disclosed therein that the subject compounds can be administered by a
transdermal device, for example using a patch either of the reservoir and
porous
membrane type or of a solid matrix variety.
U.S. Patent No. 5,607,690 to Akizawa discloses an external anti-inflammatory
and analgesic plaster preparation containing the NSAID diclofenac in the form
of its
hydroxyethylpyrrolidine salt, which is reported to exhibit enhanced skin
permeation
by comparison with an otherwise similar preparation containing diclofenac
sodium.
The low skin permeability of diclofenac sodium is stated therein to result
from the
low solubility in water of this salt.
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International Patent Publication No. WO 99/62557 discloses a composition for
transdermal administration of an NSAID comprising an absorption promoter that
consists essentially of a diethylene glycol ether and a sorbitan ester, and an
adhesive
matrix.
International Patent Publication No. WO 00/41538 discloses a composition for
transdermal administration of a drug comprising a blend of two or more acrylic-
based
polymers having differing functionalities.
International Patent Publication No. WO 00/51575 discloses a transdermal
device containing a composition of an NSAm with a skin permeation enhancer
selected from fatty alcohols, e.g., oleyl alcohol and fatty acid esters, e.g.,
glyceryl
monooleate, isopropyl myristate.
International Patent Publication No. WO 97/29735 discloses a transdermal
drug delivery system comprising a dermal penetration enhancer that is an ester
sunscreen, preferably a long-chain alkyl ester of p-aminobenzoic acid,
dimethyl
p-aminobenzoic acid, cinnamic acid, methoxycinnamic acid or salicylic acid,
for
example octyl dimethyl p-aminobenzoate or octyl salicylate.
Administration of an NSAID, and more particularly of a selective COX-2
inhibitory drug, to the skin with the objective of achieving local or systemic
therapeutic effect has therefore been widely contemplated in the art. However,
there
remains a need in the art for a selective COX-2 inhibitory drug composition
that can
be shown to exhibit a sufficient rate of skin permeation of the drug to
achieve such
effect.
Where a systemic effect is desired, the composition must be capable of
delivering daily an amount of the drug by skin permeation at least equal to
the
minimum therapeutically effective daily dosage amount when the drug is given
orally
or parenterally. Furthermore, it is neither practical nor convenient to apply
a drug
over a very large area of skin to achieve this result; typically a maximum
area for
application is about 400 cm', but preferably a much smaller area of skin is
treated.
For illustration, in the case of celecoxib, a typical minimum daily dosage
amount by oral administration for an adult human is about 200 mg. A minimum
permeation rate of 500 p.g/cm2.day over an area of 400 cm2 is therefore needed
to
provide the minimum daily dosage amount of celecoxib. It is generally
desirable to
treat a much smaller area than 400 cmz, thus the minimum permeation rate
desired is
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even higher than 500 ~glcmZ.day. Even where only local delivery is desired, a
high
permeation rate is still important, because the area of skin available for
local
application is generally no greater than about 140 cm2, often much less. In
practice, a
permeation rate of at least about 10 ,ug/cm2.day, even fox the most
therapeutically
potent selective COX-2 inhibitory drugs, is desirable in the great majority of
situations.
Whether a systemic or local therapeutic effect is desired, it has therefore
remained a difficult challenge to formulate a selective COX-2 inhibitory drug
composition having therapeutic effectiveness when administered to an area of
skin no
greater than about 400 cm2.
SUMMARY OF THE INVENTION
There is now provided a dermally deliverable pharmaceutical composition
comprising a therapeutic agent in a therapeutically effective amount
solubilized in a
solubilizing amount of a pharmaceutically acceptable Garner that comprises a
low
molecular weight monohydric alcohol, wherein (a) the therapeutic agent
comprises at
least one selective COX-2 inhibitory drug or prodrug thereof, and (b) a test
sample of
the composition provides a skin permeation rate of the therapeutic agent at
least equal
to that provided by a reference solution of the therapeutic agent in 70%
aqueous
ethanol.
A "reference solution" herein is one having the same concentration of the
therapeutic agent as the test sample, up to the limit of solubility of the
therapeutic
agent in 70% aqueous ethanol. Such a reference solution is itself an
embodiment of
the present invention.
Preferably a skin permeation rate of not less than about 10 ~g/cm2.day is
provided by the test sample.
There is further provided a dermally deliverable pharmaceutical composition
comprising a therapeutic agent solubilized in a solubilizing amount of a
pharmaceutically acceptable carrier that comprises a low molecular weight
monohydric alcohol, wherein the therapeutic agent comprises at least one
selective
COX-2 inhibitory drug or prodrug thereof and is present at a concentration in
the
composition of about 12.5 to about 400 mg/ml.
There is still further provided a dermally deliverable pharmaceutical
composition comprising a therapeutic agent solubilized in a solubilizing
amount of a
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pharmaceutically acceptable Garner that comprises a low molecular weight
monohydric alcohol, wherein the therapeutic agent comprises valdecoxib and/or
a
prodrug thereof and is present at a concentration in the composition of about
0.5 to
about 400 mg/ml.
In preferred compositions of the invention, the carrier further comprises a
skin
permeation enhancer.
There is still further provided a method of effecting targeted delivery of a
selective COX-2 inhibitory drug to a site of pain and/or inflammation in a
subject, the
method comprising topically administering a pharmaceutical composition as
provided
herein to a skin surface of the subject, preferably at a locus overlying or
adjacent to
the site of pain and/or inflammation.
There is still further provided a method of effecting systemic treatment of a
subject having a COX-2 mediated disorder, the method comprising transdermally
administering a pharmaceutical composition as provided herein, preferably by
contacting the composition with an area of skin of the subject not greater
than about
400 cm2.
DETAILED DESCRIPTION OF THE INVENTION
A dermally deliverable pharmaceutical composition of the invention
comprises a therapeutic agent solubilized in a solubilizing amount of a
pharmaceutically acceptable carrier that comprises a Low molecular weight
monohydric alcohol. For example, the therapeutic agent can be present at an
unsaturated, saturated or supersaturated concentration, so long as the
therapeutic agent
remains in solubilized form for an acceptable time period between preparation
and use
when stored in a closed container at normal ambient temperature.
What constitutes an "acceptable time period" is situation dependent, but is
normally at least about 5 days, preferably at least about 30 days, more
preferably at
least about 6 months, still more preferably at least about 1 year, and most
preferably
at Least about 2 years.
Optionally, in addition to a solubilized component of the therapeutic agent as
required herein, there can be a second component of the therapeutic agent that
is
present in particulate form, dispersed in the Garner, for example in stable
suspension
therein. This second component can act as a reservoir of the therapeutic agent
to
maintain substantial saturation of the solubilized component. However, it is
generally
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preferred that substantially all of the therapeutic agent is present in
solubilized form.
The term "dermally deliverable" means that the composition is suitable for
direct application to skin and permits absorption into the skin and/or
permeation
through the skin of the agent in an amount sufficient to provide local and/or
systemic
therapeutic effect.
The therapeutic agent comprises at least one selective COX-2 inhibitory drug
or prodrug thereof. Any such selective COX-2 inhibitory drug or prodrug known
in
the art can be used.
A preferred selective COX-2 inhibitory drug useful herein is a compound of
formula (VIII):
1
~X)n R
R4 ~ A w 3
I R
R2/ ~O
(VIII)
or a prodrug or pharmaceutically acceptable salt thereof, wherein:
A is a substituent selected from partially unsaturated or unsaturated
heterocyclyl and partially unsaturated or unsaturated carbocyclic rings,
preferably a heterocyclyl group selected from pyrazolyl, furanonyl,
isoxazolyl, pyridinyl, cyclopentenonyl and pyridazinonyl groups;
X is O, S or CH2;
nis0orl;
R' is at least one substituent selected from heterocyclyl, cycloalkyl,
cycloalkenyl and aryl, and is optionally substituted at a substitutable
position with one or more radicals selected from alkyl, haloalkyl, cyano,
carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino,
alkylamino, arylamino, nitro, aIkoxyalkyl, alkylsulfinyl, halo, alkoxy
and alkylthio;
RZ is methyl, amino or aminocarbonylalkyl;
R3 is one or more radicals selected from hydrido, halo, alkyl, alkenyl,
alkynyl,
oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio,
alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl,
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aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl,
alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl,
arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl,
alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl,
aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-
alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl,
alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-
alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-
aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-
arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl,
alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl,
arylsulfonyl and N-alkyl-N-arylaminosulfonyl, R3 being optionally
substituted at a substitutable position with one or more radicals selected
from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl,
hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro,
alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio; and
R4 is selected from hydrido and halo.
Compositions of the invention are especially useful for selective COX-2
inhibitory drugs having the formula (IX):
Y~
Z
\S
R6 (IX)
where RS is a methyl or amino group, R6 is hydrogen or a Ci_4 alkyl or alkoxy
group,
X' is N or CR7 where R7 is hydrogen or halogen, and Y and Z are independently
carbon or nitrogen atoms defining adjacent atoms of a five- to six-membered
ring that
is optionally substituted at one or more positions with oxo, halo, methyl or
halomethyl
groups, or an isomer, tautomer, pharmaceutically-acceptable salt or prodrug
thereof.
Preferred such five- to six-membered rings are cyclopentenone, furanone,
methylpyrazole, isoxazole and pyridine rings substituted at no more than one
position.
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Compositions of the invention are also useful for compounds having the
formula (X):
R'
R~
(X)
where X" is O, S or N-lower alkyl; Rg is lower haloalkyl; R9 is hydrogen or
halogen;
Rl° is hydrogen, halogen, lower alkyl, lower alkoxy or haloalkoxy,
lower
aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower
aralkylaminosulfonyl, Lower heteroaralkylaminosulfonyl, or 5- or 6- membered
nitrogen-containing heterocyclosulfonyl; and R11 and Rl2 are independently
hydrogen,
halogen, lower alkyl, lower alkoxy, or aryl; and fox pharmaceutically
acceptable salts
thereof.
A particularly useful compound of formula (X) is (S)-6,8-dichloro-2-
(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.
Compositions of the invention are also useful for selective COX-2 inhibitory
5-alkyl-2-arylaminophenylacetic acids and derivatives thereof. Particularly
useful
IS compounds of this class are 5-methyl-2-(2'-chloro-6'-
fluoroanilino)phenylacetic acid
and pharmaceutically acceptable salts thereof.
Illustratively, celecoxib, deracoxib, valdecoxib, parecoxib, rofecoxib,
etoricoxib, 2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-
1-one,
(S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid, 2-(3,4-
difluorophenyl)-4-(3-hydroxy-3-methyl-I-butoxy)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone, 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid
and their
salts, more particularly celecoxib, valdecoxib, parecoxib and its salts,
rofecoxib and
etoricoxib, are useful in the method and composition of the invention.
In a presently preferred embodiment, the therapeutic agent comprises
vaIdecoxib and/or a prodrug thereof, for example parecoxib and/or a salt
thereof, such
as parecoxib sodium.
Valdecoxib used in compositions of the invention can be prepared by any
known process, for example in the manner set forth in above-cited U.S. Patent
No.
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5,633,272. Parecoxib used in compositions of the invention can be prepared by
any
known process, for example in the manner set forth in above-cited U.S. Patent
No.
5,932,598. Other selective COX-2 inhibitory drugs can be prepared by any known
process, including processes set forth in patent publications disclosing such
drugs; for
example in the case of celecoxib in above-cited U.S. Patent No. 5,466,823 or
in U.S.
Patent No. 5,892,053 to Zhi et al., incorporated herein by reference.
According to a first embodiment of the invention, the composition exhibits a
skin permeation rate of the therapeutic agent at least equal to that provided
by a
reference solution of the therapeutic agent in 70% aqueous ethanol, preferably
a rate
of not less than about 10 p,g/cm2.day. When a skin permeation rate or range of
such
rates is indicated herein, it will be understood to mean a rate as determined
by a
standard test, illustratively a standard test using human cadaver skin.
As an example of such a test, a Franz diffusion cell can be used having a
cadaver skin membxane of suitable area, e.g., a disk of diameter 20 mm, and a
suitable
receptor fluid, as described more particularly in the Examples below. Suitable
receptor fluids can be selected by one of skill in the art, but presently
preferred
receptor fluids are a 1% polysorbate 80 solution and a 6% polyethylene glycol
(20)
oleyl ether (oleth-20) solution. The receptor fluid is maintained at a
suitable
temperature, preferably a temperature approximating living human skin
temperature.
A receptor fluid temperature of 32°C has been found suitable. The
membrane is
oriented so that its internal surface, i.e., the surface opposite the
epidermal surface, is
placed in contact with the receptor fluid. Air bubbles are removed from the
receptor
fluid, which is then allowed to equilibrate for 30 minutes with the membrane.
A test
sample of a composition is placed in contact with the epidermal surface of the
membrane, and left in place for a desired period, for example 24 hours. At
intervals
during this period, and/or at the end of this period, concentration of one or
more
selective COX-2 inhibitory drugs is determined in the receptor fluid by a
suitable
analytical method, e.g., high performance liquid chromatography (HPLC). This
concentration is a measure of the amount of the drug or drugs that have
permeated the
skin membrane during the period of the test, and can be used to calculate a
skin
permeation rate of drug in units such as ~.~cm2.day or ~,g/cm2.hour.
It will be understood that skin membranes exhibit significant variation in
permeability, depending on source. Absolute permeation rates through such
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membranes are therefore less meaningful than relative permeation rates by
comparison with a reference composition. A standard reference composition
adopted
herein is a solution of the therapeutic agent in 70% aqueous ethanol. It has
been
found that such a reference composition, which is itself an embodiment of the
invention, commonly provides a skin permeation rate of about 10 ,ug/cm2.day or
greater, particularly if the therapeutic agent is in substantially saturated
solution in the
70% aqueous ethanol. However, a composition is not excluded from the scope of
the
present invention if in a test using a particular skin membrane it provides a
skin
permeation rate lower than 10 ~,g/cmZ.day, so Iong as the rate is at least
equal to that
exhibited in a comparative test of the reference composition using a skin
membrane
from the same source.
Preferred permeation rates depend to some extent on the therapeutic potency
of the drug or prodrug selected. In the case of celecoxib, for example, which
requires
relatively high blood levels for therapeutic effectiveness, the skin
permeation rate is
preferably not less than about 25 p,g/cm2.day, more preferably not less than
about 50
~.g/cm2.day, still more preferably not less than about 75 ~,g/cm2.day and most
preferably not less than about 100 p,g/cm'.day.
According to a second embodiment of the invention, the therapeutic agent in
the composition comprises at least one selective COX-2 inhibitory drug or
prodrug
thereof and is present in the composition at a concentration of about 12.5 to
about 400
mg/ml. Below this concentration range, for example at a concentration of 10
mg/ml
(or about 1 % by weight) the skin permeation rate for most selective COX-2
inhibitory
drugs, even in the presence of a permeation enhancer, is likely to be too low
to be
therapeutically effective. Above this concentration range, for example at a
concentration of about 40% by weight (which depending on the specific gravity
of the
composition can be equivalent to a concentration of about 420 to about 500
mg/ml), it
is likely to be very difficult to solubilize mast selective COX-2 inhibitory
drugs,
prodrugs or salts thereof.
Preferably in this embodiment the concentration of the therapeutic agent is
about 12.5 to about 375 mg/ml, more preferably 12.5 to about 250 mg/ml and
most
preferably about 12.5 to about 125 mg/ml. It will be understood by one of
skill in the
art that for a drug having a relatively high dosage requirement (e.g.,
celecoxib) the
optimum concentration is likely to be higher than fox a drug having a
relatively low
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dosage requirement (e.g., valdecoxib).
Celecoxib compositions of the present invention, to be useful for transdermal
application to give systemic delivery of the drug, preferably contain
celecoxib in a
concentration permitting a daily dosage amount of about 100 mg to about 400
mg, for
example about 250 mg to about 350 mg, illustratively about 275 mg to about 325
mg.
Preferably the concentration is such that this dosage amount can be provided
by
application of the composition one to four times a day, to a skin area of up
to about
400 cm2.
Valdecoxib compositions of the present invention, to be useful for transdermal
application to give systemic delivery of the drug, preferably contain
valdecoxib in a
concentration permitting a daily dosage amount of about 10 mg to about 100 mg,
preferably about 20 mg to about 80 mg, for example about 30 mg to about 40 mg,
illustratively about 32 mg to about 38 mg, more particularly about 34 mg to
about
36 mg. Preferably the concentration is such that this dosage amount can be
provided
by application of the composition one to four times a day, preferably one to
two times
a day, to a skin area of up to about 400 cm2, preferably about 1 cm' to about
100 cm2.
Parecoxib compositions of the present invention, to be useful for transdermal
application to give systemic delivery of valdecoxib, preferably contain
parecoxib or a
salt thereof in a concentration permitting a daily dosage amount of about 10
mg to
about 100 mg, preferably about 30 mg to about 80 mg, for example about 45 mg
to
about 75 mg, illustratively about 50 mg to about 70 mg. Preferably the
concentration
is such that this dosage amount can be provided by application of the
composition one
to four times a day, preferably one to two times a day, to a skin area of up
to about
400 cm2, preferably about 1 cm2 to about 100 cm'.
For other selective COX-2 inhibitory drugs and prodrugs, the concentration
should provide a daily dosage amount in a range known to be therapeutically
effective
for such drugs and prodrugs. Preferably, the daily dosage amount is in a range
providing therapeutic equivalence to celecoxib, valdecoxib or parecoxib in the
daily
dose ranges indicated immediately above.
According to a third embodiment of the invention, the therapeutic agent in the
composition comprises valdecoxib and/or a prodrug thereof and is present in
the
composition at a concentration of about 0.5 to about 400 mg/ml, preferably
about 0.5
to about 125 mg/ml. Concenix~ation of the therapeutic agent by weight in this
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embodiment is preferably about O.OS% to about 10%, more preferably about 0.5%
to
about 5%, particularly where the composition is to be used to effect targeted
delivery
of the therapeutic agent to a site of pain and/or inflammation from an
overlying or
adjacent skin surface.
In this third embodiment, a preferred prodrug is parecoxib or a salt thereof,
for
example parecoxib sodium.
Alternatively according to this third embodiment, the therapeutic agent can be
valdecoxib alone or in combination with another drug.
It has surprisingly been found that a composition comprising both parecoxib
or a salt thereof and a selective COX-2 inhibitory drug of low water
solubility, for
example celecoxib or valdecoxib, the skin permeation rate of the drug of low
water
solubility is greatly increased by comparison with a composition lacking the
parecoxib. Thus, in a particular embodiment, the therapeutic agent in a
composition
as described above comprises parecoxib or a salt thereof and a selective COX-2
inhibitory drug of low water solubility. According to this embodiment, the
drug of
low water solubility can illustratively be selected from celecoxib, deracoxib,
valdecoxib, rofecoxib, etoricoxib, 2-(3,5-difluorophenyl)-3-[4-
(methylsulfonyl)phenyl]-2-cyclopenten-1-one and 2-(3,4-difluorophenyl)-4-(3-
hydroxy-3-methyl-1-butyoxy)-5-[4-(methyl sulfonyl)phenyl]-3-(2H)-pyridazinone.
According to any of the above embodiments, the therapeutic agent is
preferably fully solubilized in the carrier.
The carrier comprises a pharmaceutically acceptable solvent for the
therapeutic agent. For a therapeutic agent consisting of one or more water-
soluble
drugs or prodrugs, for example parecoxib sodium, water is a preferred solvent.
For
drugs or prodrugs of low water solubility, one or more pharmaceutically
acceptable
oxganic solvents will be required. Such solvents can, for example, be selected
from
mono-, di- and polyhydric alcohols, illustratively including ethanol,
isopropanol,
n-butanol, 1,3-butanediol, propylene glycol, glycerol, glycofurol, myristyl
alcohol,
oleyl alcohol and polyethylene glycol (PEG), e.g., PEG having an average
molecular
weight of about 200 to about 800. Suitable PEGs include PEG-200, PEG-350,
PEG-400, PEG-540 and PEG-600, with PEG-400 being preferred. Some of the above
solvents can function additionally as skin permeation enhancers.
Alternatively or in addition, a pharmaceutically acceptable glycol ether
solvent
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can be used, such as those conforming to formula (XI):
R'-O-((GH2)n,0)~ R2 (XI)
wherein R' and RZ are independently hydrogen or Cl_6 alkyl, CI_6 alkenyl,
phenyl or
benzyl groups, but no more than one of R' and RZ is hydrogen; m is an integer
of 2 to
about 5; and n is an integer of 1 to about 20. It is preferred that one of Rl
and R2 is a
Cl_4 alkyl group and the other is hydrogen or a Cl_4 alkyl group; more
preferably at
least one of Rl and R2 is a methyl or ethyl group. It is preferred that m is
2. It is
preferred that n is an integer of 1 to about 4, more preferably 2.
Glycol ethers useful in compositions of the present invention typically have a
molecular weight of about 75 to about 1000, preferably about 75 to about 500,
and
more preferably about 100 to about 300. Importantly, such glycol ethers must
be
pharmaceutically acceptable and must meet all other conditions prescribed
herein.
Non-limiting examples of glycols and glycol ethers that may be used in
compositions of the present invention include ethylene glycol monomethyl
ether,
ethylene glycol dimethyl ether, ethylene glycol monoethyl ether, ethylene
glycol
diethyl ether, ethylene glycol monobutyl ether, ethylene glycol dibutyl ether,
ethylene
glycol monophenyl ether, ethylene glycol monobenzyl ether, ethylene glycol
butylphenyl ether, ethylene glycol terpinyl ether, diethylene glycol
monomethyl ether,
diethylene glycol dimethyl ether, diethylene glycol monoethyI ether,
diethylene glycol
diethyl ether, diethylene glycol divinyl ether, ethylene glycol monobutyl
ether,
diethylene glycol dibutyl ether, diethylene glycol monoisobutyl ether,
triethylene
glycol dimethyl ether, triethylene glycol monoethyl ether, triethylene glycol
monobutyl ether, tetraethylene glycol dimethyl ether, and mixtures thereof.
See for
example Flick (1998): Industrial Solvents Handbook, 5th ed., Noyes Data
Corporation, Westwood, NJ.
A presently preferred glycol ether solvent is diethylene glycol monoethyl
ether, sometimes referred to in the art as DGME or ethoxydiglycol. It is
available for
example under the trademark TranscutolTM of Gattefosse Corporation.
According to the present invention, at Least one solvent or skin permeation
enhancer present is a low molecular weight monohydric alcohol. By "low
molecular
Weight" in this context is meant having substantially lower molecular weight
than
myristyl alcohol. Preferred low molecular weight monohydric alcohols are C2_s
monohydric alcohols, for example ethanol, isopropanol, n-butanol or DGME.
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It has surprisingly been found that an ethanol-water mixture as solvent for a
selective COX-2 inhibitory drug such as celecoxib or valdecoxib generally
gives a
greater skin permeation rate of the drug than ethanol alone. Suitable weight
ratios of
ethanol to water are from about 50/50 to about 90/10. An optimum ratio is
about
65/35 to about 75/25, for example about 70/30. Thus a composition having a
carrier
consisting of ethanol alone will typically not meet the criterion established
herein of
providing a skin permeation rate at least equal to that provided by a
reference solution
of the therapeutic agent in 70% aqueous ethanol.
Compositions of the present invention optionally comprise one or more
pharmaceutically acceptable co-solvents. Non-limiting examples of co-solvents
suitable for use in compositions of the present invention include any solvent
listed
above; N-methyl-2-pyrrolidinone (NMP); oleic and linoleic acid triglycerides,
for
example soybean oil; caprylic/capric triglycerides, for example MiglyolTM 812
of
Huls; caprylic/capric mono- and diglycerides, for example CapmulTM MCM of
Abitec; benzyl phenylformate; diethyl phthalate; triacetin; polyoxyethylene
capryIic%apric glycerides such as polyoxyethylene (8) capryIic/capric mono-
and
diglycerides, for example LabrasolTM of Gattefosse; medium chain
triglycerides;
propylene glycol fatty acid esters, for example propylene glycol laurate;
oils, for
example corn oil, mineral oil, cottonseed oil, peanut oil, sesame seed oil and
polyoxyethylene (35) castor oil, for example CremophorTM EL of BASF;
polyoxyethylene glyceryl trioleate, for example TagatTM TO of Goldschmidt;
polyoxyethylene sorbitan esters, for example polysorbate 80; and lower alkyl
esters of
fatty acids, for example ethyl butyrate, ethyl caprylate and ethyl oleate.
It is preferred to include as a component of the earner a skin permeation
enhancer.
In one embodiment, a permeation enhancer selected from terpenes, terpenoids,
fatty alcohols and derivatives thereof is present in the earner. Examples
include oleyl
alcohol, thymol, menthol, carvone, carveol, citral, dihydrocarveol,
dihydrocarvone,
neomenthol, isopulegol, 4-terpinenol, menthone, pulegol, camphor, geraniol,
a-terpineol, linalool, carvacrol, trans-anethole, isomers thereof and racemic
mixtures
thereof. Optionally more than one such permeation enhancer, for example a
fatty
alcohol and a terpene or terpenoid, can be present. Thus, in an illustrative
embodiment, a composition of the invention comprises as penetration enhancers
oleyl
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alcohol and thymol.
Fatty acids such as oleic acid and their alkyl and glyceryl esters such as
isopropyl laurate, isopropyl myristate, methyl oleate, glyceryl monolaurate,
glyceryl
monooleate, glyceryI dilaurate, glyceryl dioleate, etc. also can be used as
permeation
enhancers. Fatty acid esters of glycolic acid and its salts, for example as
disclosed in
International Patent Publication No. WO 98118416, incorporated herein by
reference,
are also useful permeation enhancers. Examples of such esters include lauroyl
glycolate, caproyl glycolate, cocoyl glycolate, isostearoyl glycolate, sodium
lauroyl
glycolate, tromethamine Iauroyl glycolate, etc. Also useful as permeation
enhancers
are lactate esters of fatty alcohols, for example lauryl lactate, myristyl
lactate, oleyl
lactate, etc. An example of a particularly preferred permeation enhancer is
glyceryl
monolaurate.
Other permeation enhancers include hexahydro-1-dodecyl-2H-azepin-2-one
(laurocapram, AzoneTM) and derivatives thereof, dimethylsulfoxide (DMSO), n-
decyl
methylsulfoxide, salicylic acid and alkyl esters thereof, e.g., methyl
salicylate,
N,N-dimethylacetamide, dimethylformamide, N,N-dimethyltoluamide,
2-pyrrolidinone and N-alkyl derivatives thereof, e.g., NMP and N-octyl-2-
pyrrolidinone, 2-nonyl-1,3-dioxolane, eucalyptol and sorbitan esters.
An illustrative carrier comprises DMSO and water in a ratio of 100:0 to about
10:90 by volume.
Another illustrative carrier comprises oleyl alcohol and propylene glycol in a
ratio of about 20:80 to about 5:95 by volume.
Yet another illustrative carrier comprises laurocapram and propylene glycol in
a ratio of about 20:80 to about 5:95 by volume.
In a particular embodiment, the Garner comprises as a permeation enhancer a
sunscreen. This can be an ester sunscreen as described, for example, in above-
cited
International Patent Publication No. WO 97/29735, incorporated herein by
reference.
Preferred permeation enhancers according to this embodiment are compounds of
formula (XII):
(CR3-CR4)n-C02R2
(R1)q I
(XII)
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where RI groups are independently hydrogen, lower alkyl, lower alkoxy,
halogen,
hydroxyl or NRSR6 groups in which RS and Rs are independently hydrogen or
lower
alkyl groups or RS and R6 together with the nitrogen atom to which they are
attached
form a 5- or 6-membered heterocyclic ring; R2 is a CS_I8 linear, branched or
cyclic
alkyl group; R3 is a hydrogen or phenyl group; R4 is a hydrogen or cyano
group; n is 0
or 1; and q is 1 or 2. R~ in a compound of formula (XII) is preferably a C5_12
alkyl
group, most preferably an isoamyl, octyl (i.e., 2-ethyIhexyl), menthyl or
homomenthyl
group.
Particularly preferred compounds of formula (XII) are alkyl esters of
p-aminobenzoic acid (PABA), p-dimethylaminobenzoic acid, 2-aminobenzoic acid,
cinnamic acid, p-methoxycinnamic acid, salicylic acid and 2-cyano-3,3-
diphenylacrylic acid, for example 2-ethylhexyl p-dimethylaminobenzoate
(Padimate
O), 2-ethylhexyl p-methoxycinnamate, 2-ethylhexyl salicylate, menthyl
salicylate,
homomenthyl salicylate (homosalate), menthyl 2-aminobenzoate and 2-ethylhexyl
2-
cyano-3,3-diphenylacrylate (octocrylene).
Compounds of formula (XII) are useful as permeation enhancers herein even
if they are not effective as sunscreens.
Alternatively.the sunscreen can be other than an ester sunscreen, for example
a
benzophenone sunscreen or modification thereof, such as 2-hydroxy-4-
methoxybenzophenone (oxybenzone), 2,2'-dihydroxy-4-methoxybenzophenone
(dioxybenzone), 5-benzoyl-4-hydroxy-2-methoxybenzenesulfonic acid
(sulisobenzone) or 1-(p-tert-butylphenyl)-3-(p-methoxyphenyl)-1,3-propanedione
(avobenzone).
Other ingredients of the carrier can include one or more excipients selected
from thickening agents, surfactants, emulsifiers, antioxidants, preservatives,
stabilizers, colors and fragrances. A skin irntation reducing agent, such as
vitamin E,
glycyrrhetic acid or diphenhydramine, can also be present.
A composition of the invention can be in any liquid or semi-solid dosage form
suitable for topical application to skin and can be formulated according to
conventional methods known in the art. A dosage form as contemplated herein is
one
that does not have as a component thereof a solid backing material, although,
following application of the composition to skin, an occluding material such
as a
dressing or bandage can, if desired, be applied over the treated area without
removing
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the composition or method of treatment thereof from the scope of the present
invention. A liquid or semi-solid dosage form of the invention can comprise a
solution, a suspension and/or an emulsion.
A suitable dosage form can be for example a cream, paste, gel, ointment,
S lotion or aerosol. The concentration of therapeutic agent in the dosage form
depends
on the selective COX-2 inhibitory drugs) or prodrug(s) in question, the
desired
dosage amount of such drugs) or prodrug(s) to be administered, the desired
frequency of administration, the selection of permeation enhancer if any, the
nature of
the dosage form and other factors.
A non-limiting illustrative paste, ointment, gel or cream is a composition of
the invention comprising at least one selective COX-2 inhibitory drug or
prodrug, at
least one solvent, at least one skin permeation enhancer and at least one
thickening
agent. Suitable thickening agents for ointments, gels and creams include
without
limitation hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC),
hydroxyethylcellulose, ethylcellulose, carboxymethylcellulose, dextran, guar
gum,
polyvinylpyrrolidone (PVP), pectin, starch, gelatin, casein, acrylic acid,
acrylic acid
esters, acrylic acid copolymers, vinyl alcohols, alkoxy polymers, polyethylene
oxide
polymers, polyethers and the like.
Illustratively such a composition can comprise amounts of these ingredients as
follows (all percentages by weight):
selective COX-2 inhibitory drug or prodrug 1.25-10%
solvents) (e.g., 70% ethanol, 30% water) 50-97%
co-solvent(s) and/or surfactants) 0-15%
skin permeation enhancer(s) 2-20%
thickening agents) 1-5%
Where the skin permeation enhancers comprise a fatty alcohol and a terpene or
terpenoid, e.g., oleyl alcohol and thymol, suitable amounts of these in the
illustrative
composition described immediately above are 2-10% by weight of the fatty
alcohol
and 1-6% by weight of the terpene or terpenoid. Amounts outside these ranges
can
also be useful in particular situations.
Certain compounds listed above as permeation enhancers can function as
topical analgesics in their own right. For example, methyl salicylate, menthol
or a
combination thereof (as found, for example, in Bengay~ products of Pfizer) can
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provide complementary analgesia when included in a composition of the present
invention. In particular, such compounds can provide early-onset, short-term
analgesia that complements the longer-term, sustained analgesic and anti-
inflammatory effects of the selective COX-2 inhibitory drug or prodrug. In
compositions of the invention comprising methyl salicylate and menthol,
suitable
amounts axe 5-30% by weight of methyl salicylate and 2-20% by weight of
menthol.
Amounts outside these ranges can also be useful in particular situations.
An embodiment of the invention is a composition suitable for application to
skin by means of an applicator such as an aerosol, a spray, a pump-pack, a
brush or a
swab. Preferably, such an applicator provides fixed or variable metered dose
application, as exemplified by a metered dose aerosol, a stored-energy metered
dose
pump or a manual metered dose pump. According to this embodiment, application
is
most preferably performed by means of a topical metered dose aerosol combined
with
an actuator nozzle shroud which together accurately control the amount and/or
uniformity of the dose applied. The shroud can help control the distance of
the nozzle
from the skin, a function that can alternatively be achieved by means of a
spacer-bar
or the like. Another function of the shroud is to enclose the treated area of
the skin in
order to prevent or limit bounce-back and/or loss of the composition.
Preferably the
area of application defined by the shroud is substantially circular in shape.
The
composition may be propelled by a pump-pack or more preferably by use of an
aerosol propellant such as a hydrocarbon or hydrofluorocarbon propellant,
nitrogen,
nitrous oxide, carbon dioxide or an ether, for example dimethyl ether.
In a particular embodiment, a cream, paste, gel, ointment, lotion or aerosol
composition of the invention comprises as a skin permeation enhancer a
sunscreen,
e.g., octyl p-dimethylaminobenzoate (octyl dimethyl PABA or Padimate O). A
suitable amount of such a sunscreen in the composition is 1-10%, preferably 2-
8%, by
weight.
In this embodiment the sunscreen can have a dual function as a sunscreen
(i.e.,
protectant against sunburn or other ultraviolet injury to skin) and permeation
enhancer
for the selective COX-2 inhibitory drug or prodrug. Where the drug or prodrug
is to
be administered for relief of pain and/or inflammation arising from such
injury, a
composition of this embodiment can be especially useful. Optionally other
typical
ingredients of sunscreen preparations can be included, such as titanium
dioxide.
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A particular feature of the present invention is that the dosage form can be
designed so that the drug penetrates the skin to deliver a therapeutically
effective
amount of the drug to a target site such as epidermal, dermal, subcutaneous,
muscular
and articular organs and tissues while maintaining systemic levels of the drug
not
greatly in excess of a minimum therapeutically effective level. Thus
pharmaceutical
compositions as described above can be used to effect targeted delivery of a
selective
COX-2 inhibitory drug to an external or internal site of pain and/or
inflammation in a
subject. According to a therapeutic method of the invention, a composition as
provided herein is topically administered to a skin surface of the subject,
preferably at
a locus overlying or adjacent to the site of pain and/or inflammation.
Pharmaceutical compositions as described above can also be used to effect
systemic treatment of a subject having a COX-2 mediated disorder. According to
a
therapeutic method of the invention, a pharmaceutical composition as provided
herein
is administered transdermally, preferably by contacting the composition with
an area
of skin of the subject not greater than about 400 cm2.
In either of the above methods, the composition according to a first
embodiment is a dermally deliverable pharmaceutical composition comprising a
therapeutic agent solubilized in a pharmaceutically acceptable carrier that
comprises a
CZ_6 monohydric alcohol, wherein the therapeutic agent comprises at least one
selective COX-2 inhibitory drug or prodrug thereof, and wherein the
composition
exhibits a skin permeation rate of the therapeutic agent at least equal to
that exhibited
by a reference solution of the therapeutic agent in 70% aqueous ethanol,
preferably a
rate of not less than about 10 p,glcm2.day, more preferably not less than
about 50
~g/cmz.day.
In either of the above methods, the composition according to a second
embodiment is a dermally deliverable pharmaceutical composition comprising a
therapeutic agent solubilized in a pharmaceutically acceptable carrier that
comprises a
CZ_6 monohydric alcohol, wherein the therapeutic agent comprises at least one
selective COX-2 inhibitory drug or prodrug thereof and is present at a
concentration
in the carrier of about 12.5 to about 400 mg/ml.
In either of the above methods, the composition according to a third
embodiment is a dermally deliverable pharmaceutical composition comprising a
therapeutic agent solubilized in a pharmaceutically acceptable carrier that
comprises a
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CZ_6 monohydric alcohol, wherein the therapeutic agent comprises valdecoxib
and/or a
prodrug thereof and is present at a concentration in the carrier of about 0.5
to about
400 mg/ml.
Therapeutic methods and compositions of the invention are useful in treatment
and prevention of a very wide range of disorders mediated by COX-2, including
but
not restricted to disorders characterized by inflammation, pain and/or fever.
Such
compositions are especially useful as anti-inflammatory agents, such as in
treatment
of arthritis, with the additional benefit of having significantly less harmful
side effects
than compositions of conventional non-steroidal anti-inflammatory drugs
(NSAIDs)
that lack selectivity for COX-2 over COX-1. In particular, compositions of the
invention have reduced potential for gastrointestinal toxicity and
gastrointestinal
irritation including upper gastrointestinal ulceration and bleeding, reduced
potential
for renal side effects such as reduction in renal function leading to fluid
retention and
exacerbation of hypertension, reduced effect on bleeding times including
inhibition of
platelet function, and possibly a lessened ability to induce asthma attacks in
aspirin-
sensitive asthmatic subjects, by comparison with compositions of conventional
NSAIDs. Thus compositions of the invention are particularly useful as an
alternative
to conventional NSA)Ds where such NSA)Ds are contraindicated, for example in
patients with peptic ulcers, gastritis, regional enteritis, ulcerative
colitis, diverticulitis
or with a recurrent history of gastrointestinal lesions; gastrointestinal
bleeding,
coagulation disorders including anemia such as hypoprothrombinemia, hemophilia
or
other bleeding problems; kidney disease; or in patients prior to surgery or
patients
taking anticoagulants.
Contemplated compositions are useful to treat a variety of arthritic
disorders,
including but not limited to rheumatoid arthritis, spondyloarthropathies,
gouty
arthritis, osteoarthritis, systemic lupus erythematosus and juvenile
arthritis.
Such compositions are useful in treatment of asthma, bronchitis, menstrual
cramps, preterm labor, tendinitis, bursitis, allergic neuritis,
cytomegalovirus
infectivity, apoptosis including HIV-induced apoptosis, lumbago, liver disease
including hepatitis, skin-related conditions such as psoriasis, eczema, acne,
burns,
dermatitis and ultraviolet radiation damage including sunburn, and post-
operative
inflammation including the following ophthalmic surgery such as cataract
surgery or
refractive surgery.
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Such compositions are useful to treat gastrointestinal conditions such as
inflammatory bowel disease, Crohn's disease, gastritis, irntable bowel
syndrome and
ulcerative colitis.
Such compositions are useful in treating inflammation in such diseases as
migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia,
Hodgkin's
disease, sclerodoma, rheuriiatic fever, type I diabetes, neuromuscular
junction disease
including myasthenia gravis, white matter disease including multiple
sclerosis,
sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis,
nephritis, hypersensitivity, swelling occurnng after injury including brain
edema,
myocardial ischemia, and the like.
Such compositions are useful in treatment of ophthalmic diseases, such as
retinitis, conjunctivitis, retinopathies, uveitis, ocular photophobia, and of
acute injury
to the eye tissue.
Such compositions are useful in treatment of pulmonary inflammation, such as
that associated with viral infections and cystic fibrosis, and in bone
resorption such as
that associated with osteoporosis.
Such compositions are useful for treatment of certain central nervous system
disorders, such as cortical demential including Alzheimer's disease,
neurodegeneration, and central nervous system damage resulting from stroke,
ischemia and trauma. The term "treatment" in the present context includes
partial or
total inhibition of demential, including Alzheimer's disease, vascular
dementia, multi-
infarct dementia, pre-senile dementia, alcoholic dementia and senile dementia.
Such compositions are useful in treatment of allergie rhinitis, respiratory
distress syndrome, endotoxin shock syndrome and liver disease.
Such compositions are used in treatment of pain, including but not limited to
postoperative pain, dental pain, muscular pain, and pain resulting from
cancer. For
example, such compositions are useful for relief of pain, fever and
inflammation in a
variety of conditions including rheumatic fever, influenza and other viral
infections
including common cold, low back and neck pain, dysmenorrhea, headache,
toothache,
sprains and strains, myositis, neuralgia, synovitis, arthritis, including
rheumatoid
arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing
spondylitis,
bursitis, burns, and trauma following surgical and dental procedures.
Such compositions are useful for treating and preventing inflammation-related
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cardiovascular disorders, including vascular diseases, coronary artery
disease,
aneurysm, vascular rejection, arteriosclerosis, atherosclerosis including
cardiac
transplant atherosclerosis, myocardial infarction, embolism, stroke,
thrombosis
including venous thrombosis, angina including unstable angina, coronary plaque
inflammation, bacterial-induced inflammation including Chlamydia-induced
inflammation, viral induced inflammation, and inflannmation associated with
surgical
procedures such as vascular grafting including coronary artery bypass surgery,
revascularization procedures including angioplasty, stmt placement,
endarterectomy,
or other invasive procedures involving arteries, veins and capillaries.
Such compositions are useful in treatment of angiogenesis-related disorders in
a subject, for example to inhibit tumor angiogenesis. Such compositions are
useful in
treatment of neoplasia, including metastasis; ophthalmological conditions such
as
corneal graft rejection, ocular neovascularization, retinal neovascularization
including
neovascularization following injury or infection, diabetic retinopathy,
macular
degeneration, retrolental fibroplasia and neovascular glaucoma; ulcerative
diseases
such as gastric ulcer; pathological, but non-malignant, conditions such as
hemangiomas, including infantile hemangiomas, angiofibroma of the nasopharynx
and avascular necrosis of bone; and disorders of the female reproductive
system such
as endometriosis.
Such compositions are useful in the treatment of pre-cancerous diseases, such
as actinic keratosis.
Such compositions are useful in prevention, treatment and inhibition of benign
and malignant tumors and neoplasia including neoplasia in metastasis, for
example in
colorectal cancer, brain cancer, bone cancer, epithelial cell-derived
neoplasia
(epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma,
gastrointestinal
cancer such as lip cancer, mouth cancer, esophageal cancer, small bowel
cancer,
stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer,
ovary
cancer, cervical cancer, lung cancer, breast cancer, skin cancer such as
squamous cell
and basal cell cancers, prostate cancer, renal cell carcinoma, and other known
cancers
that effect epithelial cells throughout the body. Neoplasias for which
compositions of
the invention are contemplated to be particularly useful are gastrointestinal
cancer,
Barrett's esophagus, liver cancer, bladder cancer, pancreatic cancer, ovarian
cancer,
prostate cancer, cervical cancer, lung cancer, breast cancer and skin cancer.
Such
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compositions can also be used to treat fibrosis that occurs with radiation
therapy.
Such compositions can be used to treat subjects having adenomatous polyps,
including those with familial adenomatous polyposis (FAP). Additionally, such
compositions can be used to prevent polyps from forming in patients at risk of
FAP.
More particularly, the compositions can be used in treatment, prevention and
inhibition of acral lentiginous melanoma, actinic keratoses, adenocarcinoma,
adenoid
cystic carcinoma, adenoma, adenosarcorna, adenosquamous carcinoma, astrocytic
tumors, bartholin gland carcinoma, basal cell carcinoma, breast cancer,
bronchial
gland carcinoma, capillary hemangioma, carcinoids, carcinosarcoma, cavernous
hemangioma, cholangiocarcinoma, chondrosarcoma, chorioid plexus papilloma or
carcinoma, clear cell carcinoma, cutaneous T-cell lymphoma (mycosis
fungoides),
cystadenoma, displastic nevi, endodermal sinus tumor, endometrial hyperplasia,
endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymoma,
epithelioid angiomatosis, Ewing's sarcoma, fibrolamellar sarcoma, focal
nodular
hyperplasia, gastrinoma, germ cell tumors, glioblastoma, glucagonoma,
hemangioblastoma, hemangioendothelioma, hemangioma, hepatic adenoma, hepatic
adenomatosis, hepatocellular carcinoma, insulinoma, intraepithelial neoplasia,
interepithelial squamous cell neoplasia, invasive squamous cell carcinoma,
Kaposi's
sarcoma, large cell carcinoma, leiomyosarcoma, Ientigo-maligna melanoma,
malignant melanoma, malignant mesothelial tumors, medulloblastoma,
medulloepithelioma, melanoma, meningioma, mesothelioma, mucoepidermoid
carcinoma, neuroblastoma, neuroepithelial adenocarcinoma, nodular melanoma,
oat
cell carcinoma, oligodendroglioma, osteosarcoma, papillary serous
adenocarcinoma,
pineal tumors, pituitary tumors, plasmacytoma, pseudosarcoma, pulmonary
blastoma,
renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous
carcinoma,
small cell carcinoma, soft tissue carcinoma, somatostatin-secreting tumor,
squamous
carcinoma, squamous cell carcinoma, submesothelial carcinoma, superficial
spreading
melanoma, undifferentiated carcinoma, uveal melanoma, venrucous carcinoma,
vipoma, well differentiated carcinoma and Wilm's tumor.
Such compositions inhibit prostanoid-induced smooth muscle contraction by
inhibiting synthesis of contractile prostanoids and hence can be of use in
treatment of
dysmenorrhea, premature labor, asthma and eosinophil-related disorders. They
also
can be of use for decreasing bone loss particularly in postmenopausal women
(i.e.,
26
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treatment of osteoporosis), and for treatment of glaucoma.
Preferred uses for compositions of the invention are for treatment of
rheumatoid arthritis and osteoarthritis, for pain management generally
(particularly
post-oral surgery pain, post-general surgery pain, post-orthopedic surgery
pain, and
acute flares of osteoarthritis), for prevention and treatment of headache and
migraine,
for treatment of Alzheimer's disease, and for colon cancer chemoprevention.
Topical application of a composition of the invention can be especially useful
in treatment of any kind of dermal disorder having an inflammatory component,
whether malignant, non-malignant or pre-malignant, including scar formation
and
ketosis, and also including burns and solar damage, for example sunburn,
wrinkles,
etc. Such compositions can be used to treat inflammation resulting from a
variety of
skin injuries including without limitation those caused by viral diseases
including
herpes infections (e.g., cold sores, genital herpes), shingles and chicken
pox. Other
lesions or injuries to the skin that can be treated with such compositions
include
pressure sores (decubitus ulcers), hyperproliferative activity in the
epidermis, miliria,
psoriasis, eczema, acne, dermatitis, itching, warts and rosacea. Such
compositions
can also facilitate healing processes after surgical procedures, including
cosmetic
procedures such as chemical peels, laser treatment, dermabrasion, face lifts,
eyelid
surgery, etc.
Besides being useful for human treatment, compositions of the invention are
also useful for veterinary treatment of companion animals, exotic animals,
farm
animals, and the like, particularly mammals including rodents. More
particularly,
compositions of the invention are useful for veterinary treatment of COX-2
mediated
disorders in horses, dogs and cats.
The present compositions can be used in combination therapies with opioids
and other analgesics, including narcotic analgesics, Mu receptor antagonists,
Kappa
receptor antagonists, non-narcotic (i.e. non-addictive) analgesics, monoamine
uptake
inhibitors, adenosine regulating agents, cannabinoid derivatives, Substance P
antagonists, neurokinin-1 receptor antagonists and sodium channel blockers,
among
others. Preferred combination therapies comprise use of a composition of the
invention with one or more compounds selected from aceclofenac, acemetacin,
s-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide,
acetylsalicylsalicylic acid, S-adenosylmethionine, alclofenac, alfentanil,
allylprodine,
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alminoprofen, aloxiprin, alphaprodine, aluminum bis(acetylsalicylate),
amfenac,
aminochlorthenoxazin, 3-amino-4-hydroxybutyric acid, 2-amino-4-picoline,
aminopropylon, aminopyrine, amixetrine, ammonium salicylate, ampiroxicam,
amtolmetin guacil, anileridine, antipyrine, antipyrine salicylate,
antrafenine, apazone,
aspirin, balsalazide, bendazac, benorylate, benoxaprofen, benzpiperylon,
benzydamine, benzylmorphine, berberine, bermoprofen, bezitramide, a-bisabolol,
bromfenac, p-bromoacetanilide, 5-bromosalicylic acid acetate, bromosaligenin,
bucetin, bucloxic acid, bucolome, bufexamac, bumadizon, buprenorphine,
butacetin,
butibufen, butorphanol, calcium acetylsalicylate, carbamazepine, carbiphene,
carprofen, carsalam, chlorobutanol, chlorthenoxazin, choline salicylate,
cinchophen,
cinmetacin, ciramadol, clidanac, clometacin, clonitazene, clonixin, clopirac,
clove,
codeine, codeine methyl bromide, codeine phosphate, codeine sulfate,
cropropamide,
crotethamide, desomorphine, dexoxadrol, dextromoramide, dezocine, diampromide,
diclofenac, difenamizole, difenpiramide, diflunisal, dihydrocodeine,
dihydrocodeinone enol acetate, dihydromorphine, dihydroxyaluminum
acetylsalicylate, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl
butyrate, dipipanone, dipyrocetyl, dipyrone, ditazol, droxicam, emorfazone,
enfenamic acid, epirizole, eptazocine, etanercept, etersalate, ethenzamide,
ethoheptazine, ethoxazene, ethylmethylthiambutene, ethylmorphine, etodolac,
etofenamate, etonitazene, eugenol, felbinac, fenbufen, fenclozic acid,
fendosal,
fenoprofen, fentanyl, fentiazac, fepradinol, feprazone, floctafenine,
flufenamic acid,
flunoxaprofen, fluoresone, flupirtine, fluproquazone, flurbiprofen, fosfosal,
gentisic
acid, glafenine, glucametacin, glycol salicylate, guaiazulene, hydrocodone,
hydromorphone, hydroxypethidine, ibufenac, ibuprofen, ibuproxam, imidazole
salicylate, indomethacin, indoprofen, infliximab, interleukin-10, isofezolac,
isoladol,
isomethadone, isonixin, isoxepac, isoxicam, ketobemidone, lcetoprofen,
ketorolac,
p-lactophenetide, lefetamine, levorphanol, lexipafant, lofentanil, lonazolac,
lornoxicam, loxoprofen, lysine acetylsalicylate, magnesium acetylsalicylate,
meclofenamic acid, mefenamic acid, meperidine, meptazinol, mesalamine,
metazocine, methadone, methotrimeprazine, metiazinic acid, metofoline,
metopon,
mofebutazone, mofezolac, morazone, morphine, morphine hydrochloride, morphine
sulfate, morpholine salicylate, myrophine, nabumetone, nalbuphine, 1-naphthyl
salicylate, naproxen, narceine, nefopam, nicomorphine, nifenazone, niflumic
acid,
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nimesulide, 5'-nitro-2'-propoxyacetanilide, norlevorphanol, normethadone,
normorphine, norpipanone, olsalazine, opium, oxaceprol, oxametacine,
oxaprozin,
oxycodone, oxymorphone, oxyphenbutazone, papaveretum, paranyline, parsalmide,
pentazocine, perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridine
hydrochloride, phenocoll, phenoperidine, phenopyrazone, phenyl
acetylsalicylate,
phenylbutazone, phenyl salicylate, phenyramidol, piketoprofen, piminodine,
pipebuzone, piperylone, pirazolac, piritramide, piroxicam, pirprofen,
pranoprofen,
proglumetacin, proheptazine, promedol, propacetamol, propiram, propoxyphene,
propyphenazone, proquazone, protizinic acid, ramifenazone, remifentanil,
rimazolium
metilsulfate, salacetamide, salicin, salicylamide, salicylamide o-acetic acid,
salicylsulfuric acid, salsalate, salverine, simetride, sodium salicylate,
sufentanil,
sulfasalazine, sulindac, superoxide dismutase, suprofen, suxibuzone,
talniflumate,
tenidap, tenoxicam, terofenamate, tetrandrine, thiazolinobutazone, tiaprofenic
acid,
tiaramide, tilidine, tinoridine, tolfenamic acid, tolmetin, tramadol,
tropesin, viminol,
xenbucin, ximoprofen, zaltoprofen, ziconotide and zomepirac (see The Merck
Index,
13th Edition (2001), Therapeutic Category and Biological Activity Index, lists
therein
headed "Analgesic", "Anti-inflammatory" and "Antipyretic").
Particularly preferred combination therapies comprise use of a composition of
the invention, for example a celecoxib or valdecoxib composition of the
invention,
with an opioid compound, more particularly where the opioid compound is
codeine,
meperidine, morphine or a derivative thereof.
The compound to be administered in combination with the selective COX-2
inhibitory drug can be formulated separately therefrom, and administered by
any
suitable route, including orally, rectally, parenterally or topically to the
skin or
elsewhere. Alternatively, the compound to be administered in combination with
the
selective COX-2 inhibitory drug can be coformulated therewith in a dermally
deliverable composition of the invention.
In an embodiment of the invention, particularly where the COX-2 mediated
condition is headache or migraine, the present selective COX-2 inhibitory drug
composition is administered in combination therapy with a vasomodulator,
preferably
a xanthine derivative having vasomodulatory effect, more preferably an
alkylxanthine
compound.
Combination therapies wherein an alkylxanthine compound is co-administered
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with a selective COX-2 inhibitory drug composition as provided herein axe
embraced
by the present embodiment of the invention whether or not the alkylxanthine is
a
vasomodulator and whether or not the therapeutic effectiveness of the
combination is
to any degree attributable to a vasomodulatory effect. The term
"alkylxanthine"
herein embraces xanthine derivatives having one or more Cl_4 alkyl, preferably
methyl, substituents, and pharmaceutically acceptable salts of such xanthine
derivatives. Dimethylxanthines and trimethylxanthines, including caffeine,
theobromine and theophylline, are especially preferred. Most preferably, the
alkylxanthine compound is caffeine.
The total and relative dosage amounts of the selective COX-2 inhibitory drug
and of the vasomodulator or alkylxanthine are selected to be therapeutically
and/or
prophylactically effective for relief of pain associated with the headache or
migraine.
Suitable dosage amounts will depend on the particular selective COX-2
inhibitory
drug and the particular vasomodulator or alkylxanthine selected. For example,
in a
combination therapy with celecoxib and caffeine, typically the celecoxib will
be
administered in a daily dosage amount of about 50 mg to about 1000 mg,
preferably
about 100 mg to about 600 mg, and the caffeine in a daily dosage amount of
about
1 mg to about 500 mg, preferably about 10 mg to about 400 mg, more preferably
about 20 mg to about 300 mg.
The vasomodulator or alkylxanthine component of the combination therapy
can be administered in any suitable dosage form by any suitable route,
including
orally, rectally, parenterally or topically to the skin or elsewhere. The
vasomodulator
or alkylxanthine can optionally be coformulated with the selective COX-2
inhibitory
drug in a single transdermal dosage form. Thus a transdermal composition of
the
invention optionally comprises both a selective COX-2 inhibitory drug and a
vasomodulatar or alkylxanthine such as caffeine, in total and relative amounts
consistent with the dosage amounts set out hereinabove.
The phrase "in total and relative amounts effective to relieve pain", with
respect to amounts of a selective COX-2 inhibitory drug and a vasomodulator or
alkylxanthine in a composition of the present embodiment, means that these
amounts
are such that (a) together these components are effective to relieve pain, and
(b) each
component is or would be capable of contribution to a pain-relieving effect if
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other component is or were not present in so great an amount as to obviate
such
contribution.
EXAMPLES
This invention will be more fully described by way of the following Examples
but is not limited to these Examples. The term "parecoxib" is used in these
Examples
in the strict sense of parecoxib acid except where otherwise indicated; for
example
"parecoxib Na" means the sodium salt of parecoxib.
As a way of measuring the skin permeation properties of selective COX-2
inhibitory drugs or prodrugs in dermally deliverable pharmaceutical
compositions, a
IO Franz diffusion cell was provided utilizing a human cadaver skin membrane
and a 1%
polysorbate 80 (TweenTM 80) solution as a receptor fluid. Frozen skin was
thawed at
room temperature and punched with a 20 mm puncher to provide a membrane. The
receptor compartment of the Franz diffusion cell was filled with the receptor
fluid and
the diffusion cell was maintained at 32°C. The membrane was mounted on
the
IS receptor compartment, covered and fastened with a clamp. Air bubbles were
removed
from the receptor fluid, which was allowed to equilibrate for 30 minutes. A
test
composition was brought into contact with the membrane. The amount of drug
which
permeated through the membrane in a 24 hour period was determined by HPLC
analysis of the receptor fluid. Each test was conducted in several replicates.
20 Example 1
Saturated solutions of celecoxib were prepared in the following solvents: 70%
aqueous ethanol (EtOH), ethanol, PEG-400 and propylene glycol (PG). The
solutions
were tested for skin permeation properties as described above, using 250 ~.l
drops of
each test solution. Results are shown in Table 1.
25 Example 2
Saturated solutions of valdecoxib were prepared and tested exactly as
described for the celecoxib solutions in Example 1. Results are shown in Table
I.
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Table 1: Skin flux from saturated celecoxib and valdecoxib solutions
Drug Celecoxib Valdecoxib
Solvent 70% EtOH PEG- PG 70% EtOH PEG- PG
EtOH 400 EtOH 400
Concentration15.2 91.4 297 33.3 12.7 7.48 210 23.6
(mg/ml)
Skin flux 15.7 5.62 ud ud 12.8 1.44 ud ud
(~Cg/cm2.day)3.83 1.49 4.96 0.54
ud = undetectable
No skin permeation of either celecoxib or valdecoxib was observed over a 24
hour period when PEG-400 or propylene glycol was used as the solvent.
Surprisingly, 70% aqueous ethanol provided greater skin flux of both celecoxib
and
valdecoxib than ethanol alone. With this solvent, skin permeation rates of
celecoxib
and valdecoxib were similar (15.7 and 12.8 ~,g/cmz.day respectively).
Example 3
A saturated solution of parecoxib sodium in 70% aqueous ethanol was
prepared and tested exactly as described for the celecoxib and valdecoxib
solutions in
Examples 1 and 2. Since different lots of skin were used to determine the skin
flux of
each compound, a standard was run on each skin lot and the data were
normalized.
Results, together with the corresponding celecoxib and valdecoxib results from
above,
are shown in Table 2.
Table 2: Skin flux from saturated solutions in 70% aqueous ethanol
Drug or Concentration Skin flux Normalized skin
prodru (mg/ml) (~cg/cm2.day)flux
(~. cma.day)
celecoxib 15.2 15.7 3.83 34.9
valdecoxib 12.7 12.8 4.96 53.4
_ 386 254 164 120.0
parecoxib
Na
Example 4
To saturated solutions of celecoxib, valdecoxib and parecoxib sodium in 70%
aqueous ethanol prepared as in Example 3 were added 5% oleyl alcohol and 3%
thymol by weight as permeation enhancers were prepared for celecoxib,
valdecoxib
and parecoxib sodium. The solutions were tested for skin permeation properties
as
described above, using 250 ~,l drops of each test solution. An enhancement
factor
was calculated by comparison with the skin flux data in Table 2 above. Results
are
shown in Table 3.
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Table 3: Skin flux from saturated solutions in 70% aqueous ethanol containing
% oleyl alcohol and 3 % thymoI
Drug or prodruSkin flux (~, Enhancement
cm .day) factor
celecoxib 21.7 4.6 1.4
valdecoxib 323 21 25
parecoxib 1210 58.0 4.8
Na
The combination of oleyl alcohol and thymol gave an especially pronounced
enhancement of skin flux in the case of valdecoxib.
5 Example 5
Saturated solutions of valdecoxib (5-1, 5-2 and 5-3) were prepared using
various solvents and permeation enhancers as carriers. The solutions were
tested for
skin permeation properties as described above. Carrier compositions are shown
in
Table 4 and valdecoxib concentration and skin flux data in Table 5.
Table 4: Carrier compositions (% by weight)
Composition5-1 5-25-3
water 30 33 30
ethanol 62 62 30
isopropanol- - 10
1,3-butanediol- - 22
oleyl alcohol5 5 5
thymol 3 - 3
Table 5: Valdecoxib concentration and skin flux
Com osition 5-1 5-2 5-3
Concentration 22.0 18.5 13.4
(m ml)
Skin flux (~.g/cm44.1 287 302 48.9
.day) 160 23.9
Example 6
Gel compositions of celecoxib and valdecoxib (each 1% by weight) were
prepared as solutions in 70% aqueous ethanol, together with 3% by weight
KlucelTM
(hydroxypropylcellulose) as a thickening agent. These were non-occlusively
tested,
using a 50 mg amount of each gel, for skin permeation as described above.
Distribution of drug in epidermis and dermis was also determined. Results are
shown
in Table 6, by comparison with the solution compositions of Examples 1 and 2.
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Table 6: Skin flux from solution and gel compositions
Dru Celecoxib Valdecoxib
Formulation Solution Gel Solution Gel
Concentration 15.2 10 12.7 10
(m ml)
Amount a lied 2S0 ~,l SO mg 2S0 ~,1 SO mg
Occlusive? yes no yes no
Skin flux (~.g/cm15.7 -t- 3.82 12.8 4.96 I 1.3
.day) 3.83 3.36 6.48
Drug in epidermis3_.92 _0.792.36 9.27 3.84 1.81
(,ug) 1.06 1.87
Drug in dermis 2.50 1.531.22 O.S43 O.S2Sud
(~Cg) O.S1
ud = undetectable
ExamQle 7
In a 67% aqueous ethanol solvent containing 5% parecoxib sodium, saturated
S solutions of celecoxib and valdecoxib were prepared. Skin fluxes of both
parecoxib
sodium and either celecoxib or valdecoxib were determined as described above.
Enhancement factors for celecoxib and valdecoxib skin flux, by comparison with
the
data in Table 2 above in absence of parecoxib sodium, were calculated. Results
are
shown in Table 7.
Table 7: Skin flux from combination compositions of parecoxib and either
celecoxib or valdecoxib
Drug com osition Celecoxib Valdecoxibparecoxib
+ parecoxib + Na
Na
celecoxib arecoxib valdecoxibarecoxib
Concentration 15.9 49.4 19.2 49.7
(mg/ml)
Skin flux (p.g/cm'.day)_183 1 S3 74.7 108 16.764.1
14.7 11.3
Enhancement factor11.5 8.4
~
Surprisingly, the presence of parecoxib sodium in the solution greatly
enhanced skin permeation of both celecoxib and valdecoxib.
Example 8
1S Gel formulations (Compositions 8-1 to 8-3) containing 2.S% or S% celecoxib
were prepared as solutions in 70% aqueous ethanol, together with 2%
hydroxypropylcellulose (KlucelTM) and 1% polysorbate 80 (TweenTM 80).
Composition 8-1 contained no HPMC, and Compositions 8-2 and 8-3 contained 3%
HPMC (MethocelTM E1SLV). The gels were tested for skin permeation properties
as
described in Example 6. Skin permeation results are shown in Table 8.
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Table 8: Skin flux from celecoxib gel compositions
CompositionCelecoxib HPMC (%) ReplicatesSkin flux (~cg/cmZ.day)
(%)
8-1 2.5 0 7 5.64 3.38
8-2 2.5 3 6 9.34 4.70
8-3 5 3 8 8.90 5.57
Example 9
Gel formulations containing 2.5% celecoxib were prepared as in Example 8,
but with further addition of 0.5% carbomer and 0.4% 2-amino-2-methyl-1-
propanol
(AMP-95TM) and with various grades of HPMC incorporated at 3%. The gels were
tested as described in Example 6, by comparison with a saturated celecoxib
solution
in 70% aqueous ethanol and a celecoxib gel (Composition 8-1) prepared as above
with no HPMC. The average amount of celecoxib found in receptor fluid after 15
hours is presented in Table 9.
Table 9: Skin permeation in IS hours from celecoxib gel compositions
Composition HPMC Celecoxib ermeation
(g. cma)
saturated in 70% 1.406 0.086
ethanol
8-1 none 1.464 0.246
9-1 3% MethocelTM 1.821 0.452
F4M
9-2 3% MethocelTM 2.511 0.959
E50LV
9-3 3% MethocelTM 1.900 0.260
E15LV
Example 10
Saturated aqueous solutions of celecoxib, valdecoxib and parecoxib were
prepared and skin flux was determined at various temperatures, as described in
previous examples, using 3 replicates. Results are presented in Table 10.
Table 10: Skin flux at different temperatures
Com C S~ o~ux
ound nce ( a,
t cm :da
ti )
(
/
l)
p o 32 C SO C
n
ra
on
~.g
m
celecoxib0.5 4.27 23.71
0.84 4.42
valdecoxib12.1 7.94 42.12
0.89 7.82
parecoxib50.8 8.62 47.16
1.94 3.70
Example 11
Gel formulations (Compositions 11-1 and 11-2) containing 2% parecoxib
sodium and excipient ingredients as shown in Table 11 were prepared as
follows.
TweenTM 80 (polysorbate 80) was mixed with water in a first container. HPMC
2910
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was added slowly to the resulting aqueous mixture until it was completely
dispersed.
Ethanol, parecoxib sodium, propylene glycol, thymol and oleyl alcohol were
mixed in
a second container. The resulting mixtuxe was added to the aqueous mixture in
the
first container and mixed well. I~IucelTM (hydroxypropylcellulose) was added
slowly
S with further mixing.
It will be seen that Compositions 11-1 and 11-2 differ in the amount of
propylene glycol they contain.
Table 11: Composition (% by weight) of gel formulations
Com osition 11-111-2
parecoxib Na 2 2
hydroxypropylcellulose3 3
HPMC 2910 3 3
polysorbate 80 1 1
propylene glycol 10 20
thymol 2 2
oleyl alcohol S S
ethanol SO 40
water 24 24
Compositions 11-1 and 11-2 were tested non-occusively for skin permeation
properties as described in previous examples, using 3 replicates. Both
compositions
wexe tested in a volume of 100 ~.I; Composition 11-1 was additionally tested
in
volumes of SO and 20 ~.1. Skin flux was recorded as shown in Table 12.
Table 12: Skin flux for gel formulations of parecoxib sodium
Com ositionVolume Skin flux ( /cml.da
( 1) )
11-2 100 27.3 7.0
11-1 100 27.7 7.6
11-1 SO 21.1 11.6
11-1 20 3.6 2.4
Examule 12
1S Liquid formulations (Compositions 12-1 and 12-2) were prepared as simple
solutions. Composition 12-1 contained 1 % celecoxib, 30% water, and 69%
ethanol,
by weight. Composition 12-2 contained 1 % celecoxib, 30% water, 59% ethanol
and
10% urea, by weight. Both compositions were tested occlusively for skin flux
in a
volume of S00 ~,1. Results are shown in Table 13.
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Table 13: Skin flux for liquid formulations of celecoxib
CompositionReplicatesSkin flux (p,g/cm
.day)
13-1 1 2.02
13-2 ~ 3 5.41 3.45
Example 13
Gel formulations (Compositions 13-1 to 13-4) containing 2% parecoxib
sodium and excipient ingredients as shown in Table 14 were prepared by the
procedure described in Example 11.
Table 14: Composition ( % by weight) of gel formulations
Com osition 14-114-214-3 14-4
parecoxib Na 2 2 2 2
hydroxypropylcellulose3 3 3 3
HPMC 2910 0 3 0 3
polysorbate 80 0 0 1 1
Oleyl alcohol 5 5 5 5
thymol 2 2 2 2
propylene glycol 10 11 11 11
ethanol 50 43 44 42
water ~ 28 31 32 31
Compositions 13-1 to 13-4 were tested for skin permeation properties as
described in previous examples, using 3 replicates. Formulations were tested
non-
occlusively in a volume of 50 ~1. Skin flux data are shown in Table 15.
Table 15: Skin flux for gel formulations of parecoxib sodium
Com ositionSkin flux ( cm
.da )
13-I 8.92 ~- 8.52
13-2 6.73 6.72
13-3 20.67 7.48
I3-4 21.1 I 1 I.62
Example 14
Saturated solutions of parecoxib acid (Compositions 14-1 to 14-4) were
prepared as shown in Table 16. After addition of parecoxib the solutions were
mixed
for 3 hours on a rotating mixer.
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Table 16: Composition ( % by weight) of parecoxib acid formulations
Composition 14-1 I4-2 14-3 I4-4
ethanol 7.0 6.5 6.5 6.5
water 3.0 3.0 3.0 3.0
parecoxib saturatedsaturatedsaturatedsaturated
acid
lauryl lactate 0.5
myr_istyl 0.5
lactate
glyceryl dilaurate saturated
Compositions 14-1 to 14-4 were tested for skin permeation properties as
described in previous examples, in a volume of 300 ~,1, using 3 replicates.
Skin flux
data are shown in Table 17.
Table 17: Skin flux for parecoxib acid solutions
CompositionSkin flux (~,g/cm
.day)
14-1 33.9 19.68
14-2 104.4 15.36
14-3 167.0 44.4
14-4 86.2 15.6
Example 15
Gel formulations (Compositions 15-1 to 15-4) containing 2% parecoxib
sodium and excipient ingredients as shown in Table 18 were prepared by the
procedure described in Example 11.
Table 18: Composition ( % by weight) of gel formulations
Com osition 15-115-2 15-315-4
parecoxib Na 2 2 2 2
hydroxypropyicellulose3 3 3 3
HPMC 2910 3 3 3 3
polysorbate 80 1 1 1 1
oleyl alcohol 5 5 5 5
thymol 2 2 2 2
lauryllactate 2 2.5 3 0
myristyllactate 2 2.5 0 3
glyceryl dilaurate1 0 2 2
propylene glycol 10 10 10 10
ethanol 40 40 40 40
water 29 29 29 29
Compositions 15-1 to 15-4 were tested for skin permeation properties as
described in previous examples> using 3 replicates. Formulations were tested
non-
occlusively in a volume of 50 ~.I. Skin flux data are shown in Table 19.
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Table 19: Skin flux for gel formulations of parecoxib sodium
CompositionSkin flux (p,g/cm
.day)
15-1 67.7 47.4
15-2 31.6 4.0
15-3 55.3 34.2
15-4 ~ 39.0 3.1
Example 16
Gel formulations (Compositions 16-1 to 16-13) containing 2% celecoxib, 2%
parecoxib or 2% parecoxib sodium, in each case with excipient ingredients as
shown
S in Tables 20A and 20B, were prepared by the procedure described in Example
11.
Table 20A: Composition (% by weight) of gel formulations
Com osition 16-116-216-3 16-416-516-6 16-7
celecoxib 2 2 2
parecoxib 2 2
parecoxib Na 2 2
carbomer 980 0.5 0.5 0.5 0.5 0.5 O.S
hydroxypropylcellulose
HPMC 2910 3 3 6 3 3 3 3
polysorbate 80 1 1 1 1 1 1 1
2-amino-2-methyl-1-propanol0.4 0.4 0.2 0.4 0.4 0.4
thymol 3 3 3 3
oleyl alcohol 5 2.5 5 5
glyceryl oleate 5 2.5 5
ethanol 65 58 50 65 58 65 60
water 28.122.133 28.122.128.1 25.1
~pH 7.508.45
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Table 20B: Composition (% by weight) of gel formulations
Composition 16-816-9 16-1016-1116-1216-13
celecoxib
parecoxib 2 2 2 2 2 2
parecoxib Na
carbomer 980 0.5
hydroxypropylcellulose 3 3 3
HPMC 2910 3 6 6 2 2 2
polysorbate 80 1 2 1 1 1 1
2-amino-2-methyl-1-propanol0.4
thymol 3 3 2 2
oleyl alcohol 5 2.5 5 5
glyceryl oleate 2.5 5
ethanol 58 65 50 65 62 62
water 22.125 33 27 23 18
pH 4.40 4.44 4.71 4.31
Compositions 16-1, 16-2, 16-9 and 16-11 to 16-13 were tested for skin
permeation properties as described in previous examples, using 3 replicates.
Formulations were tested non-occlusively in a volume of 100 ~ul. Skin flux
data are
shown in Table 21.
Table 21: Skin flux for gel formulations
CompositionSkin flux (~.
cm .day)
16-1 5.51 2.28
16-2 2.56 ~- 0.69
16-9 14.0 6.5
16-11 10.1 1.4
16-12 80.4 -~ 15.1
16-13 74.7 17.1
Example 17
Saturated solutions of celecoxib (Compositions 17-1 to 17-6) were prepared as
in previous examples, in the solvent systems shown in Table 22.
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Table 22: Composition ( % by weight) of solvent systems for celecoxib
solutions
Composition 17-117-2 17-317-4 17-517-6
ethanol 70 65 65 62 68 65
water 30 30 30 30 30 30
glyceryl oleate 5
salicylic acid 5
oleyl alcohol 5
thymol 3
sodium lauryI 2
sulfate
acetone 5
ArlacelTM 186
Compositions 17-1 to 17-6 were tested for skin permeation properties as
described in previous examples, in a volume of 300 p.I, using 3 replicates.
Skin flux
data are shown in Table 23.
Table 23: Skin flux for saturated celecoxib solutions
CompositionSkin flux (~.g/cm
.day)
17-1 2.60 2.02
17-2 I 8.21 I 1.04
17-3 6.02 2.86
17-4 14.160.48
17-5 4.05 1.29
r 17-6 4.99 1.03
Example 18
A 1 % celecoxib gel formulation was prepared having the composition shown
in Table 24. In a first container, water and polysorbate 80 were mixed, and
HPMC
was then added until the HPMC was completely dispersed. In a second container,
ethanol, celecoxib, propylene glycol and eucalyptus oil were mixed. The
resulting
mixture was poured into the mixture in the first container and mixed well.
Finally,
hydroxypropylcellulose was added slowly with mixing to form a gel.
Table 24: Composition ( % by weight) of celecoxib gel formulation
celecoxib 1.0
hydroxy ro ylcellulose3.0
HPMC 2910 3.0
polysorbate 80 1.0
propylene lycol 10.0
eucalyptus oil 0.2
ethanol 56.8
water 25.0
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The composition was tested for skin permeation properties as described in
previous examples. The gel formulation was tested non-occlusively in a volume
of
100 ~,1. A skin flux of 7.58 ~ 1.19 ~.g/cm2.day was determined for the 1%
celecoxib
gel formulation.
Example 19
Saturated solutions of celecoxib and of valdecoxib were prepared in 70%
aqueous ethanol. The solutions were tested for skin permeation properties as
described in previous examples, using skin from different donors 1--4 and 6.
The
effect of skin donor on skin flux of celecoxib and valdecoxib from these
solutions is
shown in Table 25.
Table 25: Effect of skin donor on skin flux of celecoxib and valdecoxib
Ski Sin flux
d (~, cm
.day)
onor celecoxibvaldecoxib
n
1 15.7
3.8
2 12.8
5.0
3 73.711.8 91.915.0
4 31.99.6 58.311.0
6 50.4
12.7
Example 20
A prototype parecoxib sodium gel formulation was prepared by methods
hereinabove described, having a composition as shown in Table 26.
Table 26: Prototype parecoxib sodium gel formulation
Ingredient Prototype
gel
( % b wei
ht)
parecoxib Na 2
hydroxypropylcellulose3
thymol 1
oleyl alcohol 3
myristyl lactate2
lauryl lactate 2.5
glyceryl dilaurate0.5
butylene glycol 6
pro ylene glycol4
ethanol 46
water 30
42
